Dose Dispensing Containers

ABSTRACT

Internally pierced formed blisters containing fluid compositions for use in devices to produce a spray or mist delivery of the compositions include internal piercing nozzles that can have significantly reduced channel volume to increase pressure of the fluid forced through the nozzle and provide finer control of spray geometry. The piercing nozzles are configured to deliver the contents of the blister to the central nervous system through the nasal olfactory epithelium.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. Ser. No. 12/233,661,filed Sep. 15, 2011 and issued as U.S. Pat. No. 8,683,995, which is acontinuation in part of application of U.S. Ser. No. 12/694,849, filedJan. 27, 2010; which is a divisional application of U.S. Ser. No.12/121,644, filed May 15, 2008, now U.S. Pat. No. 7,669,597; and alsoclaims priority to U.S. Provisional No. 60/978,619, filed Oct. 9, 2007,and U.S. Provisional No. 60/938,379, filed May 16, 2007, each of whichis hereby incorporated by reference in their entirety for all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

N/A

BACKGROUND OF THE INVENTION

There is a growing interest in delivering drugs, proteins, peptides andstem cells or other diagnostic or therapeutic active agents to the brainand central nervous system intranasally, known as nose to braindelivery. Conventional systemic delivery of agents intended for activityin the brain is problematic because drugs in the general circulationmust bypass the blood brain barrier in order to reach the brain. Thisnecessitates high dose levels to achieve results and increased sideeffects. Direct delivery to the brain or spinal cord throughintracerebroventricular or intraparenchymal injection is invasive,involves higher risk and is expensive. Direct injections become muchmore difficult when multiple treatments are required.

A number of drugs, proteins, peptides and stem cells have been shown tobe active in human and animal brains when administered nasally,including insulin, deferoxamine, progesterone, L-dopa and Glialcell-line derived neurotrophic factor (GDNF) among others. Delivery ofpowders or liquid formulated active agents has been accomplished bydrops, atomizing or inhalation devices, however the most effective, ormost convenient method of administration is by nasal delivery of anaerosol, spray stream or mist to the cribriform plate, olfactory andtrigeminal neuronal pathways.

There is a need, therefore, for packaging and delivery devices formeasured dosages of active agent(s) in which the liquid or powdercomponents of the agent(s) can be stored with a long and sterile shelflife, either in separate chambers and then mixed with a liquid oranother active agent just prior to use, or in single or multiplechambers of the same components for convenient delivery of multipledoses or applications, and in particular for delivery to the brain in anon-invasive, safe and relatively economical manner.

BRIEF SUMMARY OF INVENTION

It is an aspect of the present disclosure that devices disclosed hereinhave particular utility to deliver certain substances directly to thecentral nervous system (CNS) intranasally. Intranasal delivery is adirect, non-invasive, delivery route that bypasses the blood brainbarrier, and results in rapid delivery along the olfactory andtrigeminal nerve pathways. The disclosed devices are configured todeliver an aerosol spray, mist or stream to the cribriform plate orolfactory epithelium, wherein olfactory receptors provide a channel tothe olfactory bulb and from there directly to the brain. This deliverymethod thus offers certain advantages over systemic delivery, includingsimplified administration for the patient or caregiver, a more rapidnon-invasive delivery and reduction of systemic exposure of the drug tonon-targeted organs, resulting in fewer side effects.

Many types of pharmaceuticals or active agents can be delivered to thebrain or CNS by the intranasal delivery devices and methods disclosedherein in liquids or powder formulations, including nano and microparticulate powders, for example. Liquid formulations can includesolutions, colloids, suspensions, dispersions, and emulsions, includingmicroemulsions and nanoemulsions, for example. Such agents or activesinclude but are not limited to small molecules, proteins, peptides,hormones, chelators, stem cells, nucleic acids, liposomes, or minerals.Exemplary agents include L-dopa, insulin, deferoxamine, Glial cell-linederived neurotrophic factor (GDNF), peptides derived fromactivity-dependent neuroprotective protein (ADNP), melanocortin,oxytocin, leptin, nerve growth factor (NGF), adult stem cells,oligonucleotides, plasmids, and neurotrophic factors such asbrain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor(CNTF), and neurotrophin-4/5 (NT-4/5).

The present disclosure can be described therefore, in certainembodiments as a system, device or method for delivering apharmaceutical composition to the central nervous system of a subject bydelivering the pharmaceutical to a nasal cavity of the subject, and incertain embodiments to the cribriform plate, trigeminal nerve bundle orolfactory epithelium of the nasal cavity. It is understood that deliveryof an effective volume is a volume that is effective to cover thesurface area of the nasal passages and deliver the targetedconcentration of the active agent, or more particularly of the olfactoryepithelium, trigeminal nerve bundle or cribriform plate region. A normalhuman adult's nasal cavity has a volume of about 25 cm³ and theolfactory region occupies 8% of the nasal cavity surface area.Intranasal drug delivery volumes of 0.4 mL administered in 100 μLaliquots are known to be effective to achieve CNS effects in humans and200 mL administered in 100 μL aliquots are also contemplated. A unitdosage form of the present disclosure for intranasal delivery to theCNS, therefore can be of any effective volume and can include but is notlimited to volumes of from 0.1 μl to 1 ml, or 0.5 μl, 1 μl, 2 μl, 3 μl,4 μl, 5 μl, 6 μl, 7 μl, 8 μl, 9 μl, 10 μl, 20 μd, 30 μl, 40 μp, 50 μl,60 μl, 70 μl, 80 μl, 90 μl, 100 μl, 150 μl, 200 μl, 250 μl, 300 μl, 350μl, 400 μl, 450 μl, 500 μl, 600 μl, 700 μl, 800 μl, 900 μl, or 1 ml, andcan include one or more blister compartments for simultaneous orsequential delivery as described herein. Powder compositions can requirelarger volumes and can be delivered in volumes of from about 5 mg toabout 50 mg.

The disclosure also includes devices for nasal delivery to the CNS andmethods of treatment of CNS disorders that include but are not limitedto dementia, including Alzheimer's disease, vascular dementia, Lewy bodydementia, frontal temporal dementia, Huntington's disease andcombinations thereof, stroke, brain tumors, loss of brain cells,Parkinson's, hemorrhage, ALS, psychological disorders, schizophrenia,depressive disorders, attention deficit disorders, behavioral disorders,sleep disorders, pain, weight regulation, hormonal issues, trauma,traumatic brain injury, epilepsy, autism, post-traumatic stressdisorder, ischemia, cancer, and infections, for example.

The present disclosure is directed to formed blister delivery packagesfor use in delivery devices that hold the blister in place andforcefully crush the blister to deliver a stream, drops, spray or mistin a desired volume and spray geometry through an internalpiercer/delivery device. As used herein an internal piercer or piercingdevice or internally pierced blister refers to a crushable container inwhich a needle or other formed piercer/nozzle object is wholly containedin the crushable container so that when the container is crushed, theneedle or piercer/nozzle penetrates one surface of the container andprovides a channel for delivery of the contents of the container throughthe piercing device.

The disclosure can be described therefore in certain embodiments as aninternally pierced, formed blister including a blister formed from astretched flexible film material into a recess with an open end; apierceable surface sealed to the open end of the blister to form aninternal chamber enclosed by the formed recess; and a piercing nozzlewholly contained in the internal chamber. The piercing nozzle includes abase, including an upper surface, a lower surface and a body, anelongated, substantially cylindrical member comprising exterior wallsand projecting from the base at a first end and forming a swirl chamberand a discharge nozzle at a second end opposite the base attachment end;a solid central column in the interior of the elongated member,extending from the base to the swirl chamber; one or more internalchannels formed in the interior of the elongated member between thecentral column and the exterior walls and providing a fluid connectionbetween the base and the swirl chamber, and one or more inlet openingsin the upper surface of the base and one or more inlet channelsproviding a fluid connection from the one or more inlet openings to theone or more internal channels in the elongated member to provide a fluidpath from the internal chamber, through the base, into the internalchannels of the piercing nozzle, through the swirl chamber and out thedischarge nozzle.

In certain embodiments, the solid central column can be a separatelymanufactured piece that is added to the piercing nozzle after it isformed. In this way, a nozzle can be configured with or without thecentral column depending on the desired spray geometry. Thus in certainembodiments the piercing nozzle is constructed of two pieces, and thecentral column of the piercing nozzle comprises a separate solidelongated member sized to be inserted into a hollow interior of theelongated member.

The piercing nozzle can also include one or more channels formed in theinner surface of the elongated member, each providing a liquid path froman inlet opening to the swirl chamber. The piercing nozzle, therefore,can include one or more, or in certain embodiments, two inlet openingsin the base, each in fluid communication with an inlet channel, whereinthe inlet channels are each in fluid communication with an internalchannel disposed on opposite sides of the central column, and whereinthe two internal channels connect to the swirl chamber at opposite sidesof the chamber and wherein the openings from the internal channels intothe swirl chamber are configured to create a vortex in the swirl chamberwhen a fluid is forced through the internal channels and into the swirlchamber under pressure. The piercing nozzle can also include two inletopenings in the base, each in fluid communication with an inlet channel,wherein the inlet channels are each in fluid communication with aninternal channel disposed on opposite sides of the central column, andwherein the two internal channels connect to the swirl chamber atopposite sides of the chamber and wherein the openings from the internalchannels into the swirl chamber direct a fluid flow tangentially fromopposite sides of the swirl chamber to create a rotating, swirling orcross flow pattern in the swirl chamber. The internal channels can alsobe said to enter the swirl chamber at respective angles effective toproduce a clockwise or a counterclockwise flow pattern in the swirlchamber when a fluid is forced through the internal channels underpressure.

In certain embodiments of the internally pierced formed blistersdisclosed herein, the fluid path from the internal chamber of theblister into the internal channels comprises one or more bends and caninclude at least one 90° bend. The piercing nozzle, furthermore, can beheld in position in the internal chamber of the blister by a close fitof the base with the shape of the recess opposite the piercable surfaceand wherein the position includes the discharge nozzle proximate thepiercable surface. The blister can further include a liquid or powderedcomposition contained in the internal chamber. In certain embodiments,the composition and the internal chamber are sterile until released andcan include a pharmaceutical composition.

It is understood that the piercing nozzle described above can be usedwith any of the dosage forms, blisters or blister strips shown ordescribed herein without limitation as desired either in a blistercontaining the composition to be delivered or in a dispensing blisterchamber that the composition flows through during use.

The present disclosure can also be described as providing drug orpharmaceutical dosage forms for use in delivery devices that deliver astream, drops, spray or mist in a desired volume and spray geometry to ahuman or non-human animal. The dosage forms can be used, for example, todeliver a measured dose of a pharmaceutical or medical composition tothe nasal passages, to the eye, to the mouth, into the ear, into thelungs, into the throat, or to a topical location of a user. In preferredembodiments a predetermined quantity of a pharmaceutical or medicalcomposition comprising a fluid or a solid such as a dried powder iscontained in, or produced in an ampul or blister dosage form that iscrushed by a plunger with sufficient force to drive the dosage formagainst a piercing mechanism, piercing the dosage form and forcing theliquid or solid contents from the dosage form and through a deliverychannel into a spray to be directed to the user. A predeterminedquantity refers, in most instances, to a single dose of medication or apharmaceutical or medical composition, and in certain embodiments to aprescribed dose. A predetermined quantity of fluid or solid dosage formmay also be a partial dose when delivery of a dose is administered intwo or more spray events.

Any pharmaceutical agent or other composition that is deliverable in apowder or liquid form is contemplated in the present disclosure,including but not limited to antibiotics, antipyretics,anti-inflammatories, biologics, vitamins, co-factors, enzymes,inhibitors, activators, nutrients, vaccines including DNA based killedor live virus or microorganisms, nucleic acids, proteins, peptides,antibodies, peptide mimetics, biosimilars, opioids or other agents orpharmaceutical compositions known in the art. The pharmaceuticalcompositions are in the form of a liquid, a powder, a lyophilized agent,or any combination thereof, and include one or more active agents, whichmay be combined or mixed with pharmaceutically acceptable carriers,solvents, diluents, preservatives, surfactants, salts, adjuvants,viscosity agents, buffers, chelators, absorption enhancers or otheringredients known to those in the art as needed.

In certain embodiments, the substance dispensed from the devicesdisclosed herein is an active pharmaceutical ingredient (API), includingbut not limited to the following therapeutic compounds:anti-glaucoma/IOP (intra-ocular pressure) lowering compounds (e.g.,β-adrenoceptor antagonists, such as carteolol, cetamolol, betaxolol,levobunolol, metipranolol, timolol; miotics, such as pilocarpine,carbachol, physostigmine; sympathomimetics, such as adrenaline,dipivefrine; carbonic anhydrase inhibitors, such as acetazolamide,dorzolamide; and prostaglandins, such as PGF-2 alpha); anti-microbialcompounds, including anti-bacterials and anti-fungals, e.g.,chloramphenicol, chlortetracycline, ciprofloxacin, framycetin, fusidicacid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin,propamidine, tetracycline, tobramycin, quinolines; anti-viral compounds,e.g., acyclovir, cidofovir, idoxuridine, interferons; aldose reductaseinhibitors, e.g., tolrestat; anti-inflammatory and/or anti-allergycompounds, e.g., steroidal compounds such as betamethasone, clobetasone,dexamethasone, fluorometholone, hydrocortisone, prednisolone, andnon-steroidal compounds such as antazoline, bromfenac, diclofenac,indomethacin, lodoxamide, saprofen, sodium cromoglycate; artificialtear/dry eye therapies, comfort drops, irrigation fluids, e.g.,physiological saline, water, or oils; all optionally containingpolymeric compounds such as acetylcysteine, hydroxyethylcellulose,hydroxymellose, hyaluronic acid, polyvinyl alcohol, polyacrylic acidderivatives; diagnostics, e.g., fluorescein, rose bengal; localanesthetics, e.g., amethocaine, lignocaine, oxbuprocaine,proxymetacaine; compounds that assist healing of corneal surfacedefects, e.g., cyclosporine, diclofenac, urogastrone and growth factorssuch as epidermal growth factor; mydriatics and cycloplegics, e.g.,atropine, cyclopentolate, homatropine, hysocine, tropicamide; compoundsfor the treatment of pterygium, such as mitomycin C, collagenaseinhibitors (e.g., batimastat); compounds for the treatment of maculardegeneration and/or diabetic retinopathy and/or cataract prevention; andcompounds for systemic effects following absorption into the bloodstreamafter ocular, intranasal, or otic administration, e.g., chemical drugs,proteins and peptides such as pain medication for migraine or chronicpain management, vaccines, insulin, histamines, corticosteroidsdecongestants, and hormones.

In certain embodiments, the substance is particularly well suited forintranasal delivery, including but not limited to FluMist (Mediimmune),Imitrex (Glaxo), Migranal (Xcel), Miacalcin (Novartis), Nascobal Gel(Nastech/Questcor), Nicotrol (Pfizer), Stadol NS (Bristol-Myers-Squibb),Stimate (Aventis Behringer), Synarel (Pfizer), Zomig (AstraZeneca),Apomorphine (Britannia Pharm), Apomorphine (Nastech), Emitasol(Questor), Fentanyl (West Pharm), FluINsure (ID Biomedical), Fortical(Unigene), Hypnostat (Questcor), Insulin (Bentley Lab), Interferons(Nastech), Ketamine (IDDS), Leuprolide (West), Migrastat (Questor),Morphine (West), Morphine Gluconate (Nastech), Nascobal Spray(Questcor), Somatropin (Nastech), Peptide YY 3-36 (Nastech), PH948(Pheriin), PH180 (Organon/Pherin), Triptan (Nastech), and Vaccines(West). In still other preferred embodiments, the substance is avaccine, for example a vaccine to diphtheria, tetanus, acellularpertussis, Influenza, Herpes Simplex, Hepatitis A, Hepatitis B,Hepatitis C, Measles, Mumps, Rubella, Pneumoccal conjugate, Polio,Anthrax, Rabies, Typhoid, Yellow fever, and Attenuvax (Merck).

Other embodiments contemplated by the present disclosure include precisedelivery of volumes of non-pharmaceutical materials, e.g., reagents,compounds, diluents, solvents, and catalysis agents for assay ordiagnostic systems, test kits, or for use in industrial operations suchas precision manufacturing of specialty materials, etc. In otherembodiments, delivery of precise volumes of consumer products iscontemplated, e.g., perfumes, cosmetics, lotions, and other topicallyapplied, over the counter products.

In certain embodiments when the dosages are intended to be delivered oradministered to a human subject, the preferred agents, e.g., matrixmaterials, therapeutic agent, active agent, plasticizer, surfactant, andfunctional excipients of the present disclosure are pharmaceuticallyacceptable materials. As used herein, “pharmaceutically acceptablecarrier” or “pharmaceutically acceptable materials” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, absorption enhancingagents and the like. The use of such media and agents forpharmaceutically active agents is well known in the art. Except insofaras any conventional media or agent is incompatible with the activeagent, its use in the therapeutic compositions is contemplated.Supplementary active agents can also be incorporated into thecompositions. The phrase “pharmaceutically acceptable” also refers tomolecular entities and compositions that do not produce an allergic orsimilar untoward reaction when administered to a human or animal.

This present disclosure can be described in certain embodiments as adosage form for delivery of a pharmaceutical composition, in which thedosage form includes a first dosage chamber containing a first componentof the pharmaceutical composition, a second dosage chamber containing asecond component of the pharmaceutical composition, and a dispensingchamber that includes a piercable membrane. The second dosage chamberand the dispensing chamber may be two separate chambers, or the samechamber. The piercable membrane is a section of the membrane that isdesigned to be pierced by a piercing mechanism or device. The piercablemembrane may include an area that is weakened by scoring, or thinned,effective to inhibit production of loose pieces of the membrane duringuse as it is penetrated, and to promote a seal of the pierced membraneto outer walls of the piercing tip. The dosage form also comprises aseal, for example first delamination seal, that prevents mixing of thecontents of the first dosage chamber with the contents of the seconddosage chamber, and may comprise a second delamination seal thatprevents mixing of the contents of the second chamber with thedispensing chamber. The dosage form may further comprise a permanentseal, wherein the permanent seal surrounds the outer perimeter of allthe chambers, and in which the first and second delamination seals haveless adhesion than the permanent seal, such that the first and seconddelamination seals delaminate under significantly less pressure than thepermanent seal.

As used herein, the term “dosage chamber”, which encompasses the term“dosage blister chamber”, refers to a compartment of the discloseddosage forms that contain a component or a portion of the finalpharmaceutical composition. A dosage chamber can contain a liquid or asolid composition, to be mixed with other components to form the finalpharmaceutical composition when the contents of the chambers arecombined during or just prior to administration. A “dispensing chamber”,which encompasses the term “dispensing blister chamber”, refers to achamber that includes a piercable membrane and can include an internalpiercing mechanism. Delamination zones are seals that are designed tobreak or delaminate when pressure is applied to the chambers so that thecontents of the chambers can be mixed.

Certain dosage forms of the disclosure have two dosage chambersseparated by a delamination zone, or in certain embodiments by a highvapor barrier material such as aluminum foil, for example. Embodimentsalso include dosage forms with three, four, five, or more dosagechambers, the contents of all of which are mixed as the pharmaceuticalcomposition is delivered. The chambers can contain liquids or solids inany combination, however, in preferred embodiments, the finalpharmaceutical composition is in liquid form. In certain embodiments oneor more or even all of the dosage chambers can contain the samecomposition, or aliquots portions of the same composition when thevolume of a dose is too large to fit within a single dosage chamber. Itis an aspect of the disclosure that the dosage chambers are separatedfrom each other during storage by delamination zones, or by membranesthat can be pierced by a piercing device or burst by pressure, such thatthe barrier is removed when pressure is applied to the chambers in adelivery device, and that the final delamination or designed membranefailure is effective to allow the completed composition to enter thedispensing chamber for discharge to the site of treatment.

In certain embodiments the dispensing chamber includes an internalpiercing device. It is understood that the disclosed devices can also bedesigned for use with an external piercing mechanism that is part of thedelivery device. The internal piercing device offers several importantadvantages to the dosage form with respect to manufacturing, as well asmaintaining the sterility of the dispensing nozzle until thepharmaceutical composition is dispensed through the nozzle. Preferablythe internal piercing device is an integrated piercer nozzle dispensingsystem.

The dosage forms of the disclosure are described, therefore, in certainembodiments as including a dispensing blister chamber that contain apiercing device, wherein the piercing device is a substantially hollow,elongate member with a base end and a piercing tip opposite the base endand providing a discharge nozzle. In certain embodiments the dispensingblister conforms to at least the base end of the piercing deviceeffective to support and hold the piercing device in place duringmanufacture and use of the dosage form. The piercing devices include oneor more inlet openings on or near the base end and an internal conduitproviding fluid communication between the one or more inlet ports andthe discharge nozzle; and the surface of the internal conduit comprisesstructural features such as contours, steps, flutes, ribs,constrictions, or a combination thereof to control the spray pattern anddroplet size of a fluid forced through the piercing device. It is afurther aspect of the disclosure that the inlet openings provide a fluidpath from the interior of the dispensing blister chamber into theinternal conduit that comprises one or more bends, and that thecombination of turns in the path, which can include one or more 90°turns and the structural features of the internal conduit createvortices in the fluid as it is forced through the piercing mechanism.

It is understood that certain pharmaceutical compositions may requireadditional mixing prior to administration. This can be accomplished by auser shaking a delivery device prior to the final discharge step, or itcan be provided by the structure of the final delamination zone. Forexample, certain embodiments of the disclosure include a delaminationseal separating the dosage blister chambers from the dispensing blisterchamber that includes structural features to promote mixing of thecontents of the dosage blister chambers. Preferred structures include,but are not limited to one or more curves, a serpentine shape,constrictions, or a combination thereof. The mixing can also beaccomplished by the configuration of the piercing nozzle. For example,the nozzle configurations can further control the velocity, pressure,pattern, distribution, aim, and plume geometry of the released fluid orpowder.

In certain embodiments, therefore, the disclosure may also be describedas a piercing nozzle for dispensing a fluid or solid composition from adosage form with a particular volume, in a controlled spray pattern anddroplet size. The nozzle includes a substantially elongate member withan inlet end and a discharge end, an internal channel connecting theinlet end and the discharge end in fluid communication, one or moreinlet openings in the inlet end, a discharge opening in the dischargeend, and features on the internal chamber surface to control the spraypattern and droplet size of a fluid forced through the nozzle. The inletports are designed to provide a fluid path into the internal channelthat includes one or more right angle turns. The inlet ports can also bedesigned to produce a vortex in the liquid or solid composition as it isforced through the ports. Features in the internal channel can alsoinclude, but are not limited to, steps, flutes, ribs, constrictions,contours, and related structures to produce the desired droplet size andspray geometry. In certain embodiments, the piercing tip may be on thedischarge end of the elongated member, or on the inlet end. The piercingnozzle can be contained in a dosage form. The disclosure includes,therefore, a dosage form that comprises the piercing nozzle and apharmaceutical composition.

In certain embodiments the present disclosure can be described as aninternally pierced dosage form that includes a shaped, flexible blister,a substantially round pierceable surface sealed to the base of theshaped blister, and an internal chamber containing a piercing nozzle asdescribed herein and a liquid composition. In certain embodiments thepiercing nozzle includes a base and a piercing end, and wherein the baseis attached to the shaped blister and the piercing end is proximate thepiercable surface.

Certain aspects of the disclosure are included so that the dosage formscan be used with particular types of delivery devices. As such, incertain embodiments, any of the disclosed dosage forms can bemanufactured on a strip or disk to be dispensed sequentially. In thisway, multiple dosages can be included in a single package. Dosage formsare also designed to be used with delivery devices that perform thesteps of: compressing the dosage blister chambers, effective todelaminate the delamination seals between the dosage blister chambersand to allow the contents of the dosage blister chambers to mix orcombine; compressing the dispensing chamber effective to drive thepiercing tip through the membrane; and further compressing the dosageblister chambers effective to delaminate the delamination sealseparating the dosage blister chambers from the dispensing blisterchamber and to expel the mixed or combined pharmaceutical compositionthrough the piercing device and out the discharge nozzle.

Another embodiment of the present disclosure is a dosage form fordelivery of a pharmaceutical composition, including a first dosageblister chamber containing a first component of the pharmaceuticalcomposition; a second dosage blister chamber containing a secondcomponent of the pharmaceutical composition; and a dispensing blisterchamber comprising a piercable, pressure burstable or mechanicallyweakened membrane. This dosage form further includes a vapor barriermembrane separating the first dosage blister chamber from the seconddosage blister chamber; and a delamination seal, wherein thedelamination seal prevents mixing of the contents of the dosage blisterchambers with the dispensing chamber. In preferred embodiments thisdosage form is formed of a sheet material that has three layers in asandwich form, with two outer layers and an inner layer. The first outerlayer is preferably a high vapor barrier material that forms a membranelayer of the dosage form; the inner layer is also a high vapor barriermaterial that forms the diaphragm of the first dosage blister chamberand separates the contents of the first dosage blister chamber from thecontents of the second dosage blister chamber; and a second outer layerthat is a flexible diaphragm material that forms the diaphragm of thesecond dosage blister chamber and the dispensing blister chamber. Incertain embodiments the high vapor barrier material separating thecontents of the first dosage blister chamber from the contents of thesecond dosage blister chamber can be thinned or scored to producebreakage at a specific location when pressure is applied to the dosageblister chambers. In alternative embodiments there can also be apiercing device positioned in one of the dosage blister chamberseffective to pierce the high vapor barrier material and allow thecontents of the dosage blister chambers to mix when sufficient pressureis applied to the dosage blister chambers.

The disclosed internally pierced dosage forms can also be designed fordispensing devices that require a smaller footprint or diameter of thedosage form, such as in intranasal dispensing devices that must actuallyenter the nostril of a user, for example. In certain embodiments,therefore, a swaging, or pressure forming process is employed to foldback the seal flange of the dosage form, producing a significantlysmaller diameter package.

Certain embodiments of the disclosure, therefore, include dosage formsin which two or more components are mixed just prior to dispensing. Sucha dosage form can include a blister and a membrane, where the blister isdivided into two or more chambers. The chambers are divided by sealsthat are less adhesive than the primary seal that surrounds thecircumference of the total blister. In this embodiment, each chambercontains a solid or liquid portion of the final dose to be mixed, andpreferably at least one chamber contains a liquid such that the finalmixture is in liquid form. It is an aspect of this embodiment that thecontents of one chamber is forced into the interior of an adjacentchamber where the two components are mixed. This is accomplished byapplying a force to the first chamber that is sufficient to break theless adhesive seal between chambers without breaking the primarycircumferential seal around the blister, and crushing the first chamberto force the contents to enter the second chamber under pressure. Thesecond chamber can be composed of a flexible blister or diaphragmmaterial with the top inverted to minimize the volume of the secondchamber prior to mixing. Breaking the seal and forcing the contents ofthe first chamber into the second chamber causes the top of the chamberto pop up or expand to accommodate the contents of both chambers. Thesecond chamber, that contains or is adjacent to a piercing mechanism isthen crushed by a plunger to dispense the mixed composition. Themulti-chambered dosage form for mixing components prior to dispensingcan be essentially doughnut shaped, with one or more chambers encirclingor partially encircling a central chamber, or they may be positioned ina side by side arrangement or even stacked.

In certain embodiments, a dosage form can also include three chambers,in which a first chamber contains a liquid or powder to be mixed with aliquid or powder contained in a second chamber, with preferably at leastone component being liquid. In this embodiment, the dosage form includesa third, dispensing chamber into which the contents of the two chambersare delivered and then dispensed. A three chambered mixing dispenser caninclude two plungers, a first that crushes the dispensing chamberagainst the piercing mechanism, releasing the air from the chamberwithout compromising the sterility of the dosage. Another plungerpresses the first chamber, forcing the contents of the first chamberthrough a delamination zone and into a second chamber, mixing orcombining the contents of the dosage chambers. As the second pistoncontinues to travel, completely crushing the first and second chambers,the mixed composition is forced into and through the dispensing chamberand out the discharge nozzle in a desired spray pattern. The stepbetween mixing or combining the components and discharging thecomposition through the discharge nozzle may occur rapidly, or mayinclude a delay to allow the components to mix or combine sufficientlyprior to discharge.

The present disclosure can also be described, therefore, as a method fordispensing a pharmaceutical composition comprising two components,wherein the two components are mixed in the dosage form prior todispensing. The method includes providing a multi chambered dosage formwhere a first component is contained in a first, crushable chamber and asecond component is contained in a second, crushable chamber, and adispensing chamber that contains an internal piercing mechanism and adischarge outlet, where the first and second chamber are separated by anadhesive seal. The method further includes providing a mechanicalpressure to crush the crushable chambers, breaking the adhesive seal andforcing the contents of the crushable chambers together and forcing thecontents of the chambers through the piercing mechanism and out thedischarge outlet; where preferably at least one of the components is aliquid.

As used herein, the term “dosage form” can refer to a container for asingle or even a multiple dose of a pharmaceutical or medical agent,however the use is not limited to that use. Dosage forms as describedherein can also deliver non-medical or non-pharmaceutical compositionsin a precise quantity and a controlled spray geometry in a convenientmanner. All such uses are contemplated by the disclosure.

Throughout this disclosure, unless the context dictates otherwise, theword “comprise” or variations such as “comprises” or “comprising,” isunderstood to mean “includes, but is not limited to” such that otherelements that are not explicitly mentioned may also be included.Further, unless the context dictates otherwise, use of the term “a” or“the” may mean a singular object or element, or it may mean a plurality,or one or more of such objects or elements.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 is an embodiment of a dosage form with an internal piercingmechanism.

FIG. 2 is an embodiment of a piercing mechanism.

FIG. 3 demonstrates an embodiment of a dosage form with an internalpiercing mechanism during administration of the contents.

FIG. 4 is an embodiment of a dosage form with an internal piercingmechanism.

FIG. 5 is a view of the embodiment of FIG. 4 in the housing of a devicefor administering the dosage.

FIG. 6 is a view of the dosage form of FIG. 5 during an intermediatestep of administration.

FIG. 7 is a view of the dosage form of FIG. 5 during discharge.

FIG. 8 is a cross section view of a dosage form with two dosage chambersand an internal piercing mechanism interacting with plungers of adelivery device.

FIG. 9 is a cross section view of the dosage form of FIG. 8 in the firststep of administration.

FIG. 10 is a cross section view of the dosage form of FIG. 8 in anintermediate step of administration.

FIG. 11 is a cross section view of the dosage form of FIG. 8 duringdischarge.

FIG. 12 is an embodiment of a dual chambered dosage form on a strip forsequential administration of multiple dosages.

FIG. 13 is a cross section view of an embodiment of a dual chambereddosage interacting with pistons of a delivery device.

FIG. 14 is a cross section view the dosage form of FIG. 13 during thefirst stage of administration.

FIG. 15 is a cross section view the dosage form of FIG. 13 duringdischarge.

FIG. 16 is a perspective view of a dosage form as manufactured.

FIG. 17 is a perspective view of the dosage form of FIG. 16 formed intoa cylindrical shape for use in a delivery device.

FIG. 18 is a perspective view of the dosage form of FIG. 16 in thehousing of a delivery device.

FIG. 19 is a cross section view of the dosage form of FIG. 16 in ahousing of a delivery device in the ready mode.

FIG. 20 is a cross section view of the dosage form of FIG. 16 in thefirst step of administration.

FIG. 21 is a cross section view of the dosage form of FIG. 16 duringdischarge.

FIG. 22 is a perspective view of a dosage form with multiple dosagechambers.

FIG. 23 is a cross section view of the dosage form of FIG. 22 in ahousing of a delivery device in the ready mode.

FIG. 24 is a cross section view of the dosage form of FIG. 22 in thefirst step of administration.

FIG. 25 is a cross section view of the dosage form of FIG. 22 duringdischarge.

FIG. 26 is a perspective view of the dosage form of FIG. 22 on a stripfor sequential administration of multiple dosages.

FIG. 27 is a cross section view of an embodiment of a dual chambereddosage form in which the dosage components are separated by a high vaporbarrier material.

FIG. 28 is a cross section view of the dosage form of FIG. 27 in thefirst step of administration.

FIG. 29 is a cross section view of the dosage form of FIG. 27 duringdischarge.

FIG. 30 is a cross section view of an embodiment of a dual chambereddosage form in which the dosage components are separated by a high vaporbarrier material, and in which one of the chambers includes a piercingdevice.

FIG. 31 is a cross section view of the dosage form of FIG. 30 in themixing stage of administration.

FIG. 32 is a perspective view of an embodiment of a dosage form in whichthe final delamination zone provides structure to promote mixing of thecontents of the dosage chambers during administration.

FIG. 33 is a perspective view of a blister strip of dosage forms for usein a multi-dose dispenser.

FIG. 34 is a bottom view of the strip shown in FIG. 33.

FIG. 35 is a perspective view of a trimmed dosage form.

FIG. 36 is a side view of the dosage form shown in FIG. 35.

FIG. 37 is a view of the dosage form after swaging the rim to reduce theoutside diameter of the dosage form.

FIG. 38 is a side view of the swaged dosage form.

FIG. 39 is a view of a dosage form with a sealing depression around thesealing area.

FIGS. 40-42 are side views of embodiments of the dosage form as shown inFIG. 39.

FIG. 43 is a perspective view of a piercing nozzle.

FIG. 44 is a plan view of the bottom of a piercing nozzle with a filledcenter.

FIG. 45 is a section view of an embodiment of a piercing nozzle with afilled center and showing the fluid path through the piercing novel inuse.

FIG. 46 is a plan view of the bottom of a piercing nozzle with an opencenter.

DETAILED DESCRIPTION

Preferred embodiments of the present disclosure are directed to dosageforms that contain a measured dose of one or more pharmaceuticallyactive agents and a piercable section such that the dosage form can bepierced to release the contents under pressure. When using the term“under pressure” in the disclosure, it is understood that the pressureis typically an externally applied pressure rather than internalpressure within the dosage form itself. In typical operation, a plunger,lever, ram, wheel, or some other mechanical device contacts the dosageform with sufficient force to crush the dosage form against a piercingmember and force the contents out of the opening. The piercing membercan be either an external piercing member such as a needle, or thepiercing member can be contained within the dosage form or ampul. Thedosage form may be generated using methods well known to those of skillin the art, including, for example, form fill seal technology or blowfill seal technology. The form-fill-seal process can be used to create ablister, for example a blister pack, from rolls of flat sheet or film,filled with the pharmaceutically active agent, and closed or sealed onthe same equipment. This process involves a formed base which has thecavity in which the pharmaceutically active agent, or an agent that maybe mixed or combined with a pharmaceutically active agent, is placed,and a lidding, for example of foil, through which the agent is dispensedout of the blister. Blow fill seal technology involves forming, filling,and sealing a dosage form in a continuous process in a sterile enclosedarea inside a machine.

An example of a dosage form with an internal piercing member is shown inFIG. 1. The dosage form in FIG. 1 is a blister dosage form 1 thatincludes a diaphragm 2 formed into a dome shape and a membrane 3 sealedto the diaphragm 2 along the seal area 4. Sealed within the blisterdosage form 1 are a piercing nozzle 5 and a liquid composition 9.

The piercing nozzle of FIG. 1 is also shown in FIG. 2. This example of apiercing nozzle 5 has tapered sides 10 and an inner chamber 8 thatconnects inlet ports 7 to a discharge port 12. The inner chamber 8 cancontain internal contours 11 and other structures on the interior wallsof the inner chamber 8. The contours and other structures are designedto influence the flow of the fluid or solid agent 9. Different nozzleconfigurations are created for specific applications to cause the fluidor solid agent to exit the discharge port 12 in a spray, mist or stream,depending on the needs of a specific medication or application.

A blister dosage form is shown during use in FIG. 3. When the dose is tobe administered, the dosage form is placed in a device designed toadminister the pharmaceutical agent to a particular location, such as inthe eye, ear, nose, mouth, lungs or skin of a user, for example. Thedevice may administer the pharmaceutical agent through oral, peroral,enteral, parenteral, pulmonary, rectal, otic, topical, nasal, vaginal,lingual, direct injection, intravenous, intraarterial, intracardial,intradermal, intramuscular, intraperitoneal, intracutaneous,intraocular, ophthalmic, intranasal, intrapleural, intrathecal,intratumor, intrauterine, orthotopic, transdermal, buccal, andsubcutaneous or other routes of delivery. Many such devices include atrigger mechanism that forces a surface against the dosage form with anexplosive force to expel the contents out of the blister under pressure.Examples of such devices are described in pending U.S. application Ser.No. 11/971,471, incorporated herein in their entirety by reference. Theresults of this action are demonstrated in FIG. 3, in which a force inthe direction 15 is applied with a plunger 13 to the back of the domeddiaphragm 2. The piercing tip 6 has penetrated the membrane 3 and theliquid medication 9 has flowed into the inner chamber 8 through theinlet ports 7, out the discharge port 12 and been dispensed in adischarge pattern 14. The piercing tip 6 and tapered sides 10 of thepiercing nozzle 5 cause the membrane 3 to seal tightly around thepiercing nozzle 5 forcing the medication 9 to flow out the dischargeport 12.

Another embodiment of a blister dosage form 100 is shown in FIG. 4. Thisversion has the inlet ports 107 on the same side of the piercing nozzle105 as the discharge port 112. This configuration forces the components109 to flow through two 90° bends during dispensing. Forcing the liquidor solid agent to flow through this series of bends in conjunction withthe contours 111 in the inner chamber 108 control the discharge pattern114. In blister dosage form 100 a portion 116 of diaphragm 102 is formedto conform to the shape of the base 120 of the piercing nozzle. Thediaphragm provides support for and holds the piercing nozzle 105 inplace during assembly and during dispensing. Thus, the diaphragmfunctions to capture the piercing nozzle and hold it in place throughmanufacture and actual use.

Blister dosage form 100 is shown in FIG. 5 positioned in a housing 18with plunger 13 in the ready mode. Housing 18 has a discharge opening 19to allow the piercing nozzle 105 to penetrate the membrane 103 duringdispensing. As shown in FIG. 6, a force in direction 15 is applied toplunger 13 during the dispensing action, compressing the diaphragm 102and driving the piercing nozzle 105 into the membrane 103 at piercingpoint 20. The next stage of dispensing is shown in FIG. 7. As the forcecontinues to drive the plunger 13 against the diaphragm 102, thediaphragm collapses, driving piercing membrane 103 through the membraneand forcing the agent 109 through the piercing nozzle 105 and out thedischarge port 112 in the discharge pattern 114. In this embodiment, theshape of the blister dosage form 100 is designed to conform to theplunger 13 and housing 18 of the dosing mechanism to insure that thediaphragm 102 seals to the piercing nozzle 105 in the contact area 116and that the membrane 103 seals to the piercing nozzle 105 around thesealing area 21 in order to achieve the desired spray pattern 114.

In certain embodiments, the disclosure is directed to dosage forms thatcontain more than one pharmaceutical agent in separate chambers, or morethan one component of a medication that is to be mixed or combined justprior to or during administration. The chambers may also have onepharmaceutical agent and a second component that is to be mixed orcombined with the agent prior to administration. The pharmaceuticalagents and mixing agents in separate chambers may be liquidcompositions, solid compositions, or one or more liquid compositions andone or more solid compositions. The solid compositions may be, forexample, powdered pharmaceutical compositions or lyophilizedcompositions. The pharmaceutical or mixing agents in the chambers aretypically different, but the same pharmaceutical agent or mixing agentmay be present in more than one chamber of the same dosage form. Anexample of a dual chambered blister dosage form 22 is shown in FIG. 8.This blister includes an outer ring shaped, or arcuate shaped chamber 23filled with a first volume of agent 46 and an inner chamber 24 filedwith a second volume of agent 47. Either agent 46 or 47 can be in powderform, but one of the two is preferably a liquid. The seal between thetwo chambers is a delamination zone 25. This area releases its sealbetween diaphragm 142 and membrane 143 at a lower pressure than thebursting strength of the diaphragm material and at lower pressure thanthe seal area 144. This concept also utilizes an outer plunger 26, whichis also essentially a round member and can move independently of theplunger 13.

The dosage form 22 is shown during the dispensing steps in FIGS. 9, 10and 11. In the first stage, the outer plunger 26 is forced against theouter chamber 23. As the critical pressure is reached, the delaminationzone 25 releases its seal and the first agent 46 is driven into theinner chamber 24 and mixes with the second agent 47. As the outerplunger 26 is completely depressed as shown in FIG. 10, and the outerchamber 23 is completely collapsed, all the first agent 46 is forcedinto the inner chamber 24, causing the diaphragm of the inner chamber 24to expand to a domed shape containing the contents of both chambers. Acomparison of FIGS. 9 and 10 illustrates this expansion, as the sides ofthe inner chamber are concave (in the two dimensional drawing) in FIG. 9and expand to a convex shape in FIG. 10. The final stage is demonstratedin FIG. 11, where the force is applied to the inner plunger 13 so thatit presses the piercing nozzle 145 through the membrane 143 andcollapses the inner chamber 24, expelling the mixture of first agent 46and second agent 47 through the inner chamber 148 and out the dischargeport 212 in the desired discharge pattern 214. The seal between contactarea 116 and the sealing area 221 again force all the agents to passthrough the piercing nozzle 145, resulting in the desired sprayconfiguration.

In certain embodiments, a dosage form that contains two separatedcomponents can be manufactured on a dosage strip 27 as shown in FIG. 12.The strip can be used in an appropriate dispensing device to deliverrepeated doses of the pharmaceutical agent or mixture comprising one ormore pharmaceutical agents. Each unit of the strip includes a firstdosage chamber 28 connected to a second dosage chamber 29 by a firstdelamination zone 31 and a dispensing chamber 30 connected to the seconddosage chamber 29 by a second delamination zone 32. A unit of the dosagestrip 27 is shown in FIG. 13 as if positioned in a housing 218 withfirst plunger 33 which operates independently of second plunger 34.First chamber 28 contains a first component 146 of a pharmaceuticaldose, and second chamber 29 contains a second component 147. The housing18 includes a discharge opening 219 positioned in front of piercingnozzle 165. In the first stage of dispensing the combined agent(s) asshown in FIG. 14, a first force 35 pushes the first plunger 33,collapsing the dispensing chamber 30, and driving the piercing nozzle165 through the membrane 163. A second force 36 then pushes the secondplunger 34 against the first dosage chamber 28, causing the firstdelamination zone 31 to release its seal and causing the first component146 to mix with the second component 147. As shown in FIG. 15, when thesecond plunger 34 is completely depressed, it causes the collapse of thecombined chambers and drives the agent mixture through the dispensingchamber 30, through the piercing nozzle 165 and out discharge port 212in discharge pattern 214.

An alternative dual chamber blister dosage form 337 is shown in FIG. 17.The dosage form 337 includes a first dosage chamber 328, a firstdelamination zone 331, a second dosage chamber 329, a seconddelamination zone 332 and a dispensing chamber 330. The blister can bemanufactured as a flat piece as shown in FIG. 16, and folded into acircular shape as shown in FIG. 17 to for use with a cylindrical housingfor dispensing. FIG. 18 shows a portion of a dispensing device that hastwo independently operated plungers 333, 334 adjacent the dosage form.As shown in FIG. 19 the first plunger 333 contains a sloped cam surface338 and is positioned against the dispensing chamber 330 and the firstdosage chamber 328. When sufficient force 315 is applied to the firstplunger 333, as shown in FIG. 20, the plunger collapses the dispensingchamber 330, and drives the piercing nozzle 305 through the membrane 303and, simultaneously, forces the collapse of a portion of first dosagechamber 328 separating first delamination zone 331 and mixing theagents. When the second plunger 334 is fired, as shown in FIG. 21, itcauses the collapse of the remaining portion of the first dosage chamber328 and also crushes the second dosage chamber 329, releasing the seconddelamination zone 332, and driving the mixed components out of piercingnozzle 305 in discharge pattern 314.

An embodiment of a multi-chambered dosage form 439 is shown in FIG. 22.This embodiment can be used for medications that have more than twoagent components to mix into a single dose. The dosage form in FIG. 22,for example can be used to mix four separate components. Between thefour component chambers 428 and 440 are three initial delamination zones441. A final delamination zone 442 connects to a discharge channel 443which in turn, connects to the dispensing chamber 430. The dosage form439 is designed for use in a housing with independently separatelyoperated plungers, 433 and 434 as shown in FIG. 23. When the agent is tobe dispensed as shown in FIG. 24, the first plunger 433 collapses thedispensing chamber 430. The second plunger 434 is driven into the firstdosage chamber 428, releasing the seal of the initial delamination zones441 and mixing the components in the resulting expanded chambercontaining all the components. As the second plunger 434 continues tofurther collapse the mixed chamber, (FIG. 25) the final delaminationzone 442 releases, and the mixed components flow through the dischargechannel 443, through the piercing nozzle 405 and are discharged in thedesired pattern 414. FIG. 26 is an illustration of multiple angleblister dosage forms 439 mounted on an angled strip 445 to enablemultiple deliveries of the mixed components.

Certain embodiments of the disclosure are designed to seal apharmaceutical agent in a blister chamber that has very low permeabilityto prevent water vapor from reaching the agent. An example of such anembodiment is shown in FIG. 27. The dual chambered blister dosage form560 utilizes a tri-layer film 546 to form the membrane and thediaphragm. The middle layer 548 and membrane layer 503 are made of highvapor barrier materials such as aluminum foil. The top layer 547 is madefrom flexible diaphragm material. The first dosage chamber 528 is formedbetween the top layer 547 and the middle layer 548. The second dosagechamber 529 is formed between the middle layer 548 and the membrane 503such that the agent in the second dosage chamber 529 is hermeticallysealed from the liquid agent in the first dosage chamber 528. The seconddosage chamber 529 is separated from the dispensing chamber 530 by adelamination zone 525.

In the initial step of dispensing the components as shown in FIG. 28 afirst force 535 is applied to the first plunger 533 collapsing thedispensing chamber 530 and driving the piercing nozzle 505 through thedischarge opening 519 in the housing 518. A second force 536 is appliedto the second plunger 534 causing first dosage chamber 528 to compressand produce a break 549 in the middle layer 548 between the first dosagechamber 528 and the second dosage chamber 529 and allowing thecomponents to mix. Break 549 can be focused at a desirable location bythinning the middle layer 548 at the desired location or by weakeningthe middle layer 548 by scribing, making a partial laser cut, or othermeans. As the second plunger 534 continues to travel, the first dosagechamber 528 is completely collapsed, forcing the delamination zone 525to open and allowing the mixed components to flow through the dispensingchamber 530 and out the piercing nozzle SOS in discharge pattern 514.

Another embodiment of a blister dosage form with a tri-layer film isshown in FIG. 30. This embodiment 660 utilizes a tri-layer film 646 witha first dosage chamber 628, a second dosage chamber 629, a delaminationzone 625 and a dispensing chamber 630, and an internal piercing member650 inside the second dosage chamber 629. The piercing member can belocated in the first dosage chamber 628 in other embodiments. Duringuse, (FIG. 31) a first force 635 is applied to first plunger 633collapsing the dispensing chamber 630 and a second force 636 is appliedto the second plunger 634 compressing the first dosage chamber 628. Thepressure in the first dosage chamber 628 presses the middle layer 648against the point of the piercing member 650 causing a break 649 in themiddle layer 648 and allowing the agents to mix. Continued travel of thesecond plunger 634 causes the complete collapse of the first dosagechamber 628, separation of the delamination zone 625, and discharge ofthe mixed components.

Another embodiment of a dual chamber dosage form that provides a greaterdegree of mixing of the two components is shown in FIG. 32. Thisembodiment 751 includes a first dosage chamber 728, a first delaminationzone 731, a second dosage chamber 729, a curved or serpentinedelamination zone 752 and a dispensing chamber 730. Pressure on thediaphragm of first dosage chamber 728 causes the separation of firstdelamination zone 731 and flow of the first agent into the second dosagechamber 729. Further pressure causes separation of the curved orserpentine delamination zone 752 and flow of the agent through thedelamination zone 752 into and through the dispensing chamber 730. Theturns in the delamination zone 752 increase the mixing of thecomponents. Additional mixing means can also be employed such asrestrictions in the flow path, separation into multiple flow paths, orother methods known to those of skill in the art.

Since the rate and method of absorption of various fluid or solid agentsare influenced by the droplet size and distribution inside the nasalcavity, it is beneficial to control this spray pattern. The surfacefeatures 74 can be designed for different types of spiral, vertical andother flow and the design can be adjusted for different viscosities ofthe fluid or solid to be dispensed. For example, surface features may beadded to create a vortex, to further mix the contents of the blister, tochange the fluid property type from laminar to turbulent or vice versaor to change fluid properties such as pressure, velocity, surfacetension or viscosity. This use of surface features to control spraypattern can also be applied to the discharge passage 55 of the piercingbody 54 of the positive displacement dosage form 50 described earlier.

In certain embodiments, a shaped blister dosage form as described hereinthat contains medication and an internal piercing nozzle, is configuredfor use in a smaller diameter dispensing mechanism, while stillproviding an accurate dose of medicine in the form of a controlledspray. A blister strip 800 including a plurality of such dosage forms801 is shown in FIG. 33. The strips include a blister material layer 802in which the dosage forms are formed, and a lid material 803 (shown onthe reverse side of the strip in FIG. 34) bonded to the blistermaterial. A concentric sealing area 804 provides a resilient seal thatis not broken when the dosage forms are crushed to deliver the containedmedication.

To successfully dispense the medication, the medication must flowthrough the piercing nozzle with enough velocity to create the desiredspray geometry. As described herein, this is accomplished by pressing onthe blister form with sufficient force to push the piercing nozzlethrough the lid material, completely crushing the dosage form andforcing the contents through the nozzle with the required velocity.During this dispensing operation, the seal of the lid material to theblister material must be strong enough that no leakage occurs prior tothe nozzle piercing the lid. The smaller size required by certain dosagesituations, such as intranasal administration present greater challengesto the seal of the lid material to the blister material.

A trimmed dosage form is shown in FIG. 35 in which a trim edge 805 isshown outside the sealing area 804, providing a smaller diameter dosageform for certain uses. A side view of the dosage form is shown in FIG.36. The dosage form can also be swaged or pressure formed in a way tofurther reduce the overall diameter without negatively impacting thestrength of the seal of the lid material to the blister material. Aswaged dosage form is shown in FIG. 37. In the swaged dosage form therim 806 is formed to further reduce the outside diameter 807.

In certain embodiments, as shown in FIG. 39, the strength of the sealarea 804 can be increased by forming a concentric depression 808 aroundthe seal area 804. As shown in side view in FIGS. 40-42, a depressioncan be formed in the lid material (FIG. 40), in the blister material(FIG. 41) or in both (FIG. 42).

An embodiment of a piercing nozzle 900 for use in an internally piercedblister is shown in FIG. 43. The nozzle includes a base 902 with anupper surface 904 and a bottom 906. Attached to and extending from thebase is an elongated member 908 that terminates in a discharge nozzle910. Inlet openings 912 are shown in the top surface 904 of the base902. The bottom surface 906 of the piercing nozzle is shown in FIG. 44.The fluid path through the base can be seen in this view. The inletopenings 912 pass through the base from the top surface to the bottomand connect to the respective inlet channels 916, which are connected tothe internal channels 914.

The fluid path through the piercing nozzle is shown in more detail inFIG. 45. This nozzle is designed to be embedded in a formed blister asdescribed herein, with the base of the piercing nozzle held in place atthe bottom or formed portion of the blister and the piercing end anddischarge nozzle at or near the piercable surface as shown in FIG. 1,for example. The blisters are used in devices that hold the blister inplace and force a ram or piston against the bottom of the blister,crushing it and forcing the fluid contents through the piercing nozzleand out the discharge opening in a precisely dosed, controlled spray ormist. As shown in the Figure, as the blister is crushed, fluid in theblister is forced into the inlet openings 912, through the inletchannels 916, up through the internal channels 914, into the swirlchamber 920 and out the discharge nozzle 922. In the cross-section view,the solid central column 918 is shown to block the fluid from thecentral channel of the elongated member, creating a higher pressurefluid path for the production of finer mists.

As described herein, the piercing nozzles can also be used with orwithout a solid central column depending on the intended use. FIG. 46 isa bottom view of an example of a piercing nozzle without the centralcolumn. In certain embodiments, a two piece piercer includes the deviceshown in FIG. 46 and a second cylindrical column is placed in theopening 922 to produce the configuration shown in the device in FIG. 45.

All of the devices and methods disclosed and claimed herein can be madeand executed without undue experimentation in light of the presentdisclosure. While the devices and methods of this invention have beendescribed in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to the devicesand/or methods and in the steps or in the sequence of steps of themethods described herein without departing from the concept, spirit andscope of the invention. All such similar substitutes and modificationsapparent to those skilled in the art are deemed to be within the spirit,scope and concept of the invention as defined by the appended claims.

1. A unit dose pharmaceutical delivery device comprising: an internallypierced formed blister comprising: a blister formed from a stretchedflexible film material into a recess with an open end; a pierceablesurface sealed to the open end of the blister to form an internalchamber enclosed by the formed recess; and a piercing nozzle whollycontained in the internal chamber, the piercing nozzle comprising: abase comprising an upper surface, a lower surface and a body, anelongated, substantially cylindrical member comprising exterior wallsand projecting from the base at a first end and forming a swirl chamberand a discharge nozzle at a second end opposite the base attachment end;one or more internal channels formed in the interior of the elongatedmember and providing a fluid connection between the base and the swirlchamber, and one or more inlet openings in the upper surface of the baseand one or more inlet channels providing a fluid connection from the oneor more inlet openings to the one or more internal channels in theelongated member to provide a fluid path from the internal chamber,through the base, into the internal channels of the piercing nozzle,through the swirl chamber and out the discharge nozzle; wherein thepiercing nozzle comprises internal structures configured to direct aliquid or powder contained in the blister to the cribriform plate,trigeminal nerve bundle or olfactory epithelium when administeredintranasally to the recipient.
 2. The unit dose pharmaceutical deliverydevice of claim 1, wherein the piercing nozzle comprises a solid centralcolumn in the interior of the elongated member, extending from the baseto the swirl chamber, between the central column and the exterior walls.3. The internally pierced formed blister of claim 1, wherein thepiercing nozzle is constructed of two pieces, and the central column ofthe piercing nozzle comprises a separate solid elongated member sized tobe inserted into a hollow interior of the elongated member.
 4. Theinternally pierced formed blister of claim 1, wherein the piercingnozzle comprises two channels formed in the inner surface of theelongated member, each connecting an inlet opening to the swirl chamber.5. The internally pierced formed blister of claim 1, wherein thepiercing nozzle comprises two inlet openings in the base, each in fluidcommunication with an inlet channel, wherein the inlet channels are eachin fluid communication with an internal channel disposed on oppositesides of the central column, and wherein the two internal channelsconnect to the swirl chamber at opposite sides of the chamber andwherein the openings from the internal channels into the swirl chamberare configured to create a vortex in the swirl chamber when a fluid isforced through the internal channels and into the swirl chamber underpressure.
 6. The internally pierced formed blister of claim 1, whereinthe piercing nozzle comprises two inlet openings in the base, each influid communication with an inlet channel, wherein the inlet channelsare each in fluid communication with an internal channel disposed onopposite sides of the central column, and wherein the two internalchannels connect to the swirl chamber at opposite sides of the chamberand wherein the openings from the internal channels into the swirlchamber direct a fluid flow tangentially from opposite sides of theswirl chamber.
 7. The internally pierced blister of claim 1, wherein thepiercing nozzle further comprises one or more channels formed in theinner surface of the elongated body connecting the inlet openings to theswirl chamber and further wherein the internal channels enter the swirlchamber at respective angles effective to produce a clockwise or acounterclockwise flow pattern in the swirl chamber when a fluid isforced through the internal channels under pressure.
 8. The internallypierced formed blister of claim 1, wherein the fluid path from theinternal chamber into the internal channels comprises one or more bends.9. The internally pierced formed blister of claim 8, wherein the one ormore bends include at least one 90° bend.
 10. The internally piercedformed blister of claim 1, wherein the piercing nozzle is held inposition in the internal chamber by a close fit of the base with theshape of the recess opposite the piercable surface and wherein theposition includes the discharge nozzle proximate the piercable surface.11. The internally pierced formed blister of claim 1, further comprisinga liquid or powdered composition contained in the internal chamber. 12.The internally pierced formed blister of claim 1, wherein thecomposition and the internal chamber are sterile.
 13. The internallypierced formed blister of claim 11, wherein the composition is aneurologically active pharmaceutical composition that is transported tothe brain via the olfactory bulb when administered to the olfactoryepithelium.
 14. The internally pierced formed blister of claim 13,wherein the composition comprises an active agent selected from a smallmolecule, protein, peptide, hormone, chelator, stem cell, nucleic acid,a mineral or combinations thereof.
 15. The internally pierced formedblister of claim 13, wherein the composition comprises L-dopa, insulin,deferoxamine, Glial cell-line derived neurotrophic factor (GDNF), apeptide derived from activity-dependent neuroprotective protein (ADNP),melanocortin, oxytocin, leptin, nerve growth factor (NOF), an adult stemcell, an oligonucleotide, a plasmid, brain-derived neurotrophic factor(BDNF), ciliary neurotrophic factor (CNTF), or neurotrophin-4/5(NT-4/5).